Overcoming current challenges to T-cell receptor therapy via metabolic targeting to increase antitumor efficacy, durability, and tolerability

Mao, Wendy

doi:10.3389/fimmu.2022.1056622

Cited by 5 publications

(3 citation statements)

References 138 publications

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“…Spermidine treatment further enhances the functions of TCR-T cells and suppresses tumor growth in a xenograft mouse model [131] . Manipulating mTOR signaling could enhance the fitness and cytotoxicity of TCR-T cells [132] . TCR-T cells supplemented with a p38 inhibitor, IL-7, and IL-15, but not IL-2, could further increase T cell proliferation, leading to a largely naïve phenotype and sustained expression of effector molecules such as granzyme B and IFN-γ [133] .…”

Section: Strategies To Improve Tcr-t Cell Therapy Beyond Tcr Engineeringmentioning

confidence: 99%

The recent advancement of TCR-T cell therapies for cancer treatment

Zhao*,

Shao,

2024

ABBS

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Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells. Adoptive cell therapy, as a form of living drug, has undergone explosive growth over the past decade. The recognition of tumor antigens by the T-cell receptor (TCR) is one of the natural mechanisms that the immune system used to eliminate tumor cells. TCR-T cell therapy, which involves introducing exogenous TCRs into patients' T cells, is a novel cell therapy strategy. TCR-T cell therapy can target the entire proteome of cancer cells. Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials, particularly in treating solid tumors. In this review, we examine the progress of TCR-T cell therapy over the past five years. This includes the discovery of new tumor antigens, protein engineering techniques for TCR, reprogramming strategies for TCR-T cell therapy, clinical studies on TCR-T cell therapy, and the advancement of TCR-T cell therapy in China. We also propose several potential directions for the future development of TCR-T cell therapy.

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Section: Strategies To Improve Tcr-t Cell Therapy Beyond Tcr Engineeringmentioning

confidence: 99%

The recent advancement of TCR-T cell therapies for cancer treatment

Zhao*,

Shao,

2024

ABBS

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“…TCR-T cell therapy also faces challenges such as treatment-associated toxicity, tumor antigen escape, low tumor infiltration and suppressive tumor milieu. 1058 Besides, identification of tumor epitope-specific TCRs is complex. The advances of high-throughput screening using peptide libraries and barcoded tetramers and scTCR-seq facilitate the identification of antigen-specific TCRs.…”

Section: T Cell-based Cancer Immunotherapymentioning

confidence: 99%

T cells in health and disease

Sun,

Su,

Jiao

et al. 2023

Sig Transduct Target Ther

228

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T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.

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“…These molecules then recruit cells with immunosuppressive function, including myeloid-derived suppressor cells (MDSCs), T regulatory (Treg) cells, innate lymphoid cells (ILCs), tumor associated macrophages (TAMs), and cancer associated fibroblasts (CAFs). This establishes an immunosuppressive TME and suppresses antigen processing and presentation ( 10 , 132 ), leading to immune evasion. Furthermore, HIFα controls the expression of checkpoint molecule programmed death-ligand 1 (PD-L1) on the surface of cancer cells and PD-1 expression on T cells, which negatively impacts T cell survival and effector functions via the PD1/PD-L1 axis ( 10 , 125 ).…”

Section: The Impact Of Tme Metabolism On Endogenous and Adaptively Tr...mentioning

confidence: 99%

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

2023

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Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies.

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Overcoming current challenges to T-cell receptor therapy via metabolic targeting to increase antitumor efficacy, durability, and tolerability

Cited by 5 publications

References 138 publications

The recent advancement of TCR-T cell therapies for cancer treatment

The recent advancement of TCR-T cell therapies for cancer treatment

T cells in health and disease

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

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